Factors implicated in high morbidity and mortality following influenza, SARS, Hanta and Ebola virus infection include robust cytokine production (cytokine storm), excessive inflammatory infiltrates (immunopathology), and virus-induced tissue destruction. Our studies with pathogenic human H1N1 influenza virus (Cell 146, 2011; PNAS 108, 2011) were the first to definitively show that cytokine storm causes, rather than associates with resultant morbidity and mortality. Infection occurs in epithelial cells and cytokine storm is initiated and amplified by pulmonary endothelial cells. Modulation of sphingosine-1-phosphate (S1P)1 receptor on pulmonary endothelial cells curtails early innate immune responses and protects the infected host significantly better (82%) than antiviral compounds (50%) while usage of antiviral therapy combined with S1P agonists afford optimal protection (96%). We demonstrated that cytokine production and leukocyte recruitment are independent occurrences, and S1P1 receptor signaling on pulmonary endothelial cells regulates both events. We uncovered that cytokine amplification depends on type 1 interferon signaling. The MRCE with its collection of investigators with interests and experience in innate immune pathways and type 1 interferon signaling provide a synergism with our proposal. Our goal is to understand how cytokine amplification is regulated. Specifically, how type 1 interferon regulates global cytokine amplification following human pandemic H1N1/2009 influenza infection. We will determine if a similar amplification loop exists in SARS infection for which preliminary evidence shows is successfully modified by S1P therapy. Our specific aims make use of currently on hand reagents to determine the subset(s) of interferon required to amplify early cytokine production, lineage tracing reporter Td-tomato and IFNAR1flox/flox mice to identify the specific cell subsets responsible for cytokine amplification and to analyze cross talk signaling pathways that are important players in cytokine storm. The future fruits of our studies are aimed at both therapeutics to control cytokine storm and markers to identify susceptible individuals to these diseases.